ABSTRACT There is a limited literature regarding factors associated with self-medication of pain and discomfort using alcohol, non-prescription substances or overuse of prescription medications among people living with Human Immunodeficiency Virus (HIV). This cross-sectional analysis used data from the Boston ARCH Cohort among participants with HIV infection and a history of alcohol or other substance use. Among 248 participants, 37% were female, 50% Black, 25% Latinx; 36% reported fair to poor health and 89% had CD4 cell counts >200/mm3. Half reported self-medication and of those, 8.8% reported doing so only with alcohol, 48.8% only with other substances and 42.4% with both alcohol and other substances. Those reporting self-medication were significantly (p < .05) younger (mean 47 vs 50 years), less employed (11% vs 21%), and less likely to have HIV viral suppression (60% vs. 80%). Depression, anxiety, and HIV symptoms were associated with significantly greater odds of self-medicating, as were substance dependence, recent injection substance use, heavy alcohol use, cocaine use, opioid use, sedative use, and cannabis use. Self-medication, highly prevalent and associated with worse mental health symptoms, greater substance use, and lesser HIV disease control, should be explored by HIV clinicians caring for people who use substances.